CN1276978C - Method of preparing 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol, methane sulfonate - Google Patents
Method of preparing 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol, methane sulfonate Download PDFInfo
- Publication number
- CN1276978C CN1276978C CNB018207529A CN01820752A CN1276978C CN 1276978 C CN1276978 C CN 1276978C CN B018207529 A CNB018207529 A CN B018207529A CN 01820752 A CN01820752 A CN 01820752A CN 1276978 C CN1276978 C CN 1276978C
- Authority
- CN
- China
- Prior art keywords
- isomer
- dihydropyrane
- compound
- reaction
- racemic mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/20—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hydrogen atoms and substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D309/22—Radicals substituted by oxygen atoms
- C07D309/24—Methylol radicals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P11/00—Preparation of sulfur-containing organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A method of producing (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate using 1,3-butadiene and a ketoethanal to form an intermediate racemic mixture. The racemic mixture is resolved to remove one isomer from the reaction product mixture. Following resolution, the following steps are performed: reduce the isomer to an alcohol, react the alcohol with triphenylmethyl chloride, ozonalyze the resulting reaction product, reduce the ozonalyzed product to yield a diol and react the diol with a methane sulfonyl compound to form (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate. Alternatively, the racemic mixture may first be reduced and the resulting racemic alcohol mixture is resolved to isolate one isomer of the alcohol and the remaining process steps are followed.
Description
Background of invention
1. invention field
The present invention relates to 3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-preparation of 4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate, more specifically, relate to the preparation of the single optical isomer of this product, comprise the fractionation of the racemic mixture of intermediate product.
2. prior art
The preparation of some drugs comprises uses 3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate (MTBS).The related compound of MTBS is disclosed among the PCT publication WO97/19080.The preparation of MTBS and related compound thereof generally includes uses relatively costly starting raw material.In these methods some are seen and are set forth in Journal ofOrganic Chemistry, the 63rd volume, and the 6th phase, 1961-1973 page or leaf (1998), wherein a synthetic route is shown in the following reaction process.In this synthetic method, obtain trityl Racemic glycidol (diagram chemical formula B) with trityl group (Tr) protection (R)-Racemic glycidol (diagram chemical formula A), open the ether that the Racemic glycidol ring obtains illustrating chemical formula C by handling with vinyl bromination magnesium.The allylation of Compound C produces the ether of diagram chemical formula D.Compound D is carried out ozone and is decomposed; carry out the glycol that sodium borohydride reduction obtains illustrating chemical formula E subsequently; (MsCl) handles it with methane sulfonyl chloride, generates (S)-3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate (diagram chemical formula F).
The preparation method of this MTBS is uneconomic on industry.Therefore, still need to use be easy to get and relatively inexpensive starting raw material prepares 3-[2-{ (methyl sulphonyl) oxygen oxyethyl group]-4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate.
Summary of the invention
Method of the present invention can satisfy these needs, according to this method, forms the S-isomer or the R-isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol by a kind of method that generates the racemic mixture of intermediate reaction product.Split the isomer that this racemic mixture optionally separates the hope of described alcohol, make the further reaction of isomer of this hope of described alcohol obtain 3-[2-{ (methyl sulphonyl) oxygen then oxyethyl group]-4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate.
Method of the present invention may further comprise the steps:
(a) make the reaction of 1,3-butadiene and ketone acetaldehyde (ketoethanal) form 2-carbonyl-3, the racemic mixture of 6-dihydropyrane compound; With
(b) with 2-carbonyl-3, the 6-dihydropyrane compound is converted into an isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol.
This method also be included in step (a) and (b) between the step of the racemic mixture of the dihydropyrane compound that produces in the enzymatic splitting step (a) with an isomer of the dihydropyrane of separating step (a) arranged.Perhaps, this racemic mixture can be converted into step (b) alcohol racemic mixture and with gained 2-carbonyl-3, the racemic mixture of 6-dihydropyrane compound carries out chemistry or enzymatic splits to separate the isomer of (3, the 6-dihydro-2H-pyrans-2-yl) methyl alcohol of wishing.
The 2-carbonyl-3 of separating step (a), the preferred method of the isomer of the hope of 6-dihydropyrane compound comprise makes described racemic mixture and lytic enzyme, preferably with proteolytic enzyme, more preferably with bacillus lentus (Bacillus lentus) mmp reaction.By reacting with lytic enzyme, the isomer of described dihydropyran derivatives optionally is hydrolyzed into carboxylic acid, thereby forms water that contains a kind of isomer and the organic phase that contains another kind of isomer.With organic phase and the water mixture that obtains containing the enantiomer-pure that is hopeful isomer separated from one another.Reduction step (b) preferably includes and makes dihydropyran derivatives and lithium aluminum hydride reaction to form alcohol.
Can further handle to generate 3-[2-{ (methyl sulphonyl) oxygen the R-or the S-isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol by following other step oxyethyl group]-4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate:
(c) alcohol and trityl group chlorine are reacted to form 3 of triphenyl methoxyl group replacement, 6-dihydropyrane;
(d) ozone decomposes 3 of triphenyl methoxyl group replacement, and the 6-dihydropyrane is to form reaction product;
(e) the described reaction product of reduction is to form glycol; With
(f) make the reaction of described glycol and sulfonyl methane based compound to form 3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-isomer of 4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate.
Step (c) can comprise add catalyzer in alcohol.In step (d), preferably the ozone bubbling is passed through 3 of triphenyl methoxyl group replacement, 6-dihydropyrane solution is not carrying out under the isolating situation to generate the solution of ozonize, and in step (e), by adding reductive agent, as sodium borohydride, it is reduced immediately.
Detailed Description Of The Invention
And then method of the present invention is included in reacts B or C after the step to generate (3 described in the reaction A; 6-dihydro-2H-pyrans-2-yl) isomer of methyl alcohol, and the optional step of D of reacting is to generate 3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-isomer of 4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate.
In reaction A, by the 1,3-butadiene of diagram represented by formula I and the ketone acetaldehyde reaction of representing by the diagram Formulae II, wherein R
1Expression hydroxyl, straight or branched C
1-C
12Alkoxyl group, unsubstituted or C
1-C
12Phenoxy group or group-NR that alkyl replaces
2R
3, R wherein
2And R
3Identical or different, be hydrogen or C
1-C
12Alkyl or R
2And R
3Be combined together to form 2-12 unit ring, wherein one or more annular atomses are heteroatoms.Preferred heteroatoms is the sulphur of alkylsulfonyl.Preferably, R
1Be hydroxyl or C
1-C
12Alkoxyl group.Compound I and II and stablizer are dissolved in a kind of suitable solvent together as quinhydrones, as heating to generate the racemic mixture of the chemical formula III compound of diagram in the toluene and in autoclave.The racemic mixture of compound III can carry out purifying by distillation or similar method.
Reaction A
In reaction B, R wherein
1Not hydroxyl, split the enantiomer of separating diagram Formulae II I by enzyme.Use lytic enzyme, the compound of handling the chemical formula III of diagram as the aqueous solution of bacillus lentus proteolytic enzyme produces and contains 3, the organic phase of the water of the R-isomer of 6-dihydropyrane-2-carboxylic acid (not shown) and the desired S-isomer represented by diagram chemical formula IV.Isolate organic phase and,,, produce (S)-(3, the 6-dihydro-2H-pyrans-2-yl) methyl alcohol of representing by diagram chemical formula V from aqueous phase as lithium aluminum hydride or PMHS (polymethyl hydrogen siloxane) reduction as using reductive agent in the tetrahydrofuran (THF) (THF) at solvent.Other reductive agents that are fit to comprise two (2-methoxy ethoxy) aluminum hydride, sodium borohydride etc.Also can use catalytic hydrogenation.
Reaction B
Another route that generates (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol isomer is shown among the reaction C.In reaction C, at solvent, in THF, use reductive agent, come from the compound III of reacting A as lithium aluminium hydride reduction, generate the racemic mixture of compound Va alcohol.In the presence of lipase, compound Va and vinyl-acetic ester or similar compounds (wherein, the R that represents by diagram chemical formula VI
4For hydrogen is C
1-C
6Alkyl) reaction generates diagram chemical formula VII acetic ester of representing and the alcohol that illustrates chemical formula V.This lipase-catalyzed reaction is further described in Journal of the American Chemical Society, the 110th volume, and the 21st phase is in the 7200-7205 page or leaf (1988).Compound V is by conventional method, as separating among distillation or the chromatogram normal complex compound VI I.Also can be by using chemical resolving agent, handle as chiral acid and compound Va to be carried out chemistry split isolating its isomer, thereby form the isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol of representing by compound V.
When being ester, compound III can use another kind of route.The ester of compound III by alkali or acid hydrolysis generate by diagram chemical formula VIII represent 3, the racemic mixture of 6-dihydropyrane-2-carboxylic acid.Use chemical resolving agent, compound VIII is handled obtaining as Chiral Amine by illustrating the optically pure acid that chemical formula IX represents.Compound I X and alcohol are as methyl alcohol or ethanol (R
5OH, wherein R
5Can be C
1-C
6Alkyl) reaction obtains by illustrating the ester that chemical formula X represents.In THF, compounds X is reduced into the optically pure alcohol of representing by diagram chemical formula V with for example lithium aluminum hydride.
In reaction B or reaction C, product is represented the isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol by diagram chemical formula V.In order to react further reaction among the D, compound V is preferably its S-isomer.But, also can produce the R-isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol by using suitable lytic enzyme or chemical resolving agent.
Reaction C
In reaction D, the solvent that the alcohol of diagram chemical formula V and trityl group chlorine (TrCl) are being fit to, as reaction in methylene dichloride and the triethylamine (TEA), the optional catalyzer that uses as 4-dimethylaminopyridine (DMAP), with (S)-trityl-(3, the 6-dihydro-2H-pyrans-2-yl) methyl ether that obtains representing by diagram chemical formula XI.I is dissolved in solvent with compounds X, in methylene dichloride and methyl alcohol, this solution is carried out the ozonize meeting cause two key ozonize in the compounds X I ether, and by reaction mixture is joined reductive agent, in sodium borohydride, intermediate can directly be reduced into the glycol of being represented by diagram chemical formula XII, (S)-and 3-(2-hydroxyl-oxethyl)-4-(triphenyl methoxyl group)-1-butanols.At alkali, under the existence as methylamine, compounds X II and methane sulfonyl chloride (MsCl) as reacting in the methylene dichloride, generate the MTBS that is represented by diagram chemical formula XIII at solvent.
Reaction D
The topmost advantage of the present invention be to use relatively inexpensive and be easy to get starting raw material, promptly 1,3-butadiene and ketone acetaldehyde prepare the isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol and further alcohol are converted into MTBS.
Although described the present invention from universal above, following embodiment will provide the further elaboration of typical method of the present invention.
Embodiment
Step 1
The toluene solutions of glyoxylic acid ethyl ester that will contain 949.4 gram solid 50% join in the reactor and stir with the speed of 500rpm.With nitrogen purging reactor and emptying, in reactor, keep the nitrogen pressure of 5psig.In reactor, add 1,3-butadiene (439.3 gram), and reaction mixture is heated to 160 ℃, make reaction carry out some hrs up to the own reaction of the glyoxylic acid ethyl ester that has 95% by gas Chromatographic Determination at least.With reactor cooling to 40 ℃, and remove vacuum.It is 80-90 ℃ reaction product that collecting reaction product, vacuum distilling obtain under 15-16 holder boiling point, yield 30-35%.Measuring this reaction product is 2-ethoxy carbonyl-3, the racemic mixture of 6-dihydropyrane.
Step 2
2-ethoxy carbonyl-3 with step 1, the racemic mixture of 6-dihydropyrane (2.5 gram) joins in the reaction flask, adds the phosphate buffer (pH is 7.5) of 7 milliliters of (ml) 0.2M and the bacillus lentus protein enzyme solution (50 milligrams of about every ml proteins) of 2ml afterwards.(23 ℃) stirred reaction mixture and to keep PH by dropping sodium be 7.5 at room temperature.After 5 hours, the enantiomeric purity of unreacted ester is 99%, and comes termination reaction by adding 10ml methyl tertiary butyl ether (MTBE), obtains water and organic phase.Transfer in the separating funnel with the pH regulator to 8.5 of water and with mixture.With the MTBE aqueous phase extracted of 20ml, merge isolated organic layer and use saturated sodium bicarbonate solution (10ml) extraction once, once with saturated nacl aqueous solution (10ml) extraction.Organic layer restrains anhydrous magnesium sulfate dryings with 2.Use the Rotary Evaporators removal of solvent under reduced pressure via the water vacuum fan, obtain the limpid yellow liquid of 1.2 gram band fragrance, yield is 48%.Gas chromatographic analysis and nucleus magnetic resonance (NMR) show product have with (S)-2-ethoxy carbonyl-3, the structure of 6-dihydropyrane unanimity.
Step 3
Under nitrogen atmosphere, in 1 liter of reactor, add the solution (260ml) of lithium aluminum hydride (10.45 gram) in THF (9.88 gram), and be cooled to-2 ℃.In 1.25 hours, in 0-6 ℃ with stir down, in reaction flask, be added dropwise to 78 gram (S)-2-ethoxy carbonyls-3 of 2 described preparations set by step, the 6-dihydropyrane is dissolved in the solution among the THF of 75ml.After the reinforced end of isomer, mixture was stirred 2 hours, meanwhile make mixture be warmed up to about 12 ℃.Dripping water (10ml), is the sodium hydroxide solution of 10 grams 15% subsequently.Mixture is also finally separated through a dense gel phase.Add entry (30ml) once more, the reinforced time is 10 minutes.Mixture was stirred 1 hour and filtered.With gained solids wash 4 times, the final THF solution of coupling vacuum stripping obtains the little yellow liquid of 52.0 grams up to its constant weight with the THF of about 50ml.The composition of assaying reaction product, it has the structure with (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol unanimity.
Step 4
(3,6-dihydro-2H-pyrans-2-yl) methyl alcohol of obtaining in the step 3 (46.06 gram) joined contain 117.23 gram trityl group chlorine, in the mixture of the TEA of 250ml methylene dichloride and 54ml and the reaction flask of stirring.Starting temperature is about 18 ℃, and is elevated to 44 ℃ in 5 minutes.Stirred 2 days with the mixture cool to room temperature and under nitrogen.With 200ml water with mixture extraction twice, and aqueous phase discarded.Organic phase is removed desolvate (methylene dichloride) with dried over mgso and coupling vacuum stripping.Add heptane (200ml), and under vacuum, stir the mixture, meanwhile remove most of methylene dichloride.Filter heptane mixture and obtain 76 gram crystal with heptane wash, measure by high pressure liquid chromatography (HPLC), its purity is 90%.
Mother liquor concentrated obtain yellow soup compound.Add Virahol (150ml), stir the mixture and it was left standstill 1.5 hours.Mixture filtered and use washed with isopropyl alcohol, drying to obtain about 15 restrain solids.These two batches of solids are merged and in about 500ml Virahol, be heated to boiling.Solution is left standstill in room temperature, be cooled to then about 15 ℃ to be settled out crystal.Mixture is filtered and wash with cold isopropanol, drying obtains 78.6 gram solids.Remaining mother liquor is merged and coupling vacuum stripping.Add TEA (5ml) with the 50ml Virahol, and mixture is at room temperature placed spend the night.Filter out precipitation, washing is also dry, obtains 9.5 gram products.From the Virahol of the every gram of about 5ml,, obtain 7 gram products with product recrystallization twice.The crystal of other product and main batch mixes.Total recovery be 85.6 the gram solids, its structure with (S)-trityl-(3,6-dihydro-2H-pyrans-2-yl) methyl ether unanimity.
Step 5
(S)-trityl in the step 4-(3,6-dihydro-2H-pyrans-2-yl) methyl ether (71.5g) is dissolved in 350ml methylene dichloride and the 250ml methanol mixture.This solution is joined 1 liter having chuck, be equipped with in the reactor of gas filter import, thermopair and dry-ice condenser.Use fluorinated liquid and dry ice, bathe system cools to-40 ℃ with circulation.The air bubbling of ozonize is by about 85 minutes of this solution, and up to the solution becomes au bleu, this shows that reaction carries out fully.Temperature is raised to-25 ℃ from-40 ℃ during ozonize.HPLC shows that reaction carries out fully.
Step 6
Stir down, the reaction mixture of step 5 is directly joined contain in the solution that 17.5 gram sodium borohydrides form in the 0.02N of 400ml sodium hydroxide.Mixture at room temperature stirs and spends the night, and at room temperature mixture is stirred in addition and gives 20 hours.HPLC shows that reaction carries out fully.Separate organic phase, and with 50ml methylene dichloride aqueous phase extracted again.Merge organic phase, coupling vacuum stripping obtains 81.8 gram thickness soup compounies.HPLC shows that this soup compound comprises 96% product, and its structure is with (S)-3-(2-hydroxyl-oxethyl)-4-(triphenyl methoxyl group)-the 1-butanols is consistent.
Step 7
81.9 gram (S)-3-(2-the hydroxyl-oxethyl)-4-solution that (triphenyl methoxyl group)-the 1-butanols forms in the 800ml methylene dichloride that will come from step 6 join 2 liters and mechanical stirrer, thermopair are housed and have in the round-bottomed flask of feed hopper of nitrogen purging device, stir the mixture, add the TEA of 87ml, obtain limpid colourless solution.Solution temperature is elevated to 23 ℃ from 21 ℃, and is cooled to 0-5 ℃ in ice bath.Under 0-5 ℃, in 80 minutes, in reaction flask, add the mixture of 43.5ml methane sulfonyl chloride and 50ml methylene dichloride.Behind reinforced the end, reaction mixture was stirred 1 hour down at 0-5 ℃.With 500ml methylene dichloride diluted reaction mixture and with 315ml water extracting twice, extract once with the 315ml sodium bicarbonate.Organic phase was also filtered with about 100 gram dried over sodium sulfate in 30 minutes.Under room temperature and 15 millibars, solid is evaporated to dried, and under 10 ℃ and 2 millibars dried overnight, obtain 111.1 gram crude products.This crude product is dissolved under 35-40 ℃ in the 345ml ethyl acetate, and (150ml 60M) filters on filter gained solution through B.Filtrate is joined 2 liters mechanical stirrer, thermopair are housed and have in the round-bottomed flask of feed hopper of nitrogen purging device, under 23 ℃, in 3.5 hours to wherein adding the 690ml heptane.After the reinforced end of heptane, mixture was at room temperature stirred 90 minutes.Filter about 5 minutes separate solid on the power funnel and obtain limpid filtrate by boosting 1.With filtrate and mother liquor washed twice solid remaining in the reaction flask is washed off.Solid is compressed several times up to collecting less than filtrate, and itself and filter cake are joined in the reaction flask that contains the 300ml heptane in the lump.Remove heptane by press filtration, filter cake is pressed several times with scraper.With 700ml pentane washing solid, filter and under nitrogen dry 1 hour, obtain the wet solid of 210 grams.Merge the mother liquor of washing process and heptane and be evaporated to driedly under room temperature and 15 millibars, it is yellow semi-solid to obtain 10.8 other grams.Collect solid and 2 millibars and 10 ℃ down dry 22 hours up to obtaining constant weight, obtain 96.7 and restrain products, measure its structure and (S)-3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-4-(triphenyl methoxyl group)-the 1-1-butanol, methane sulfonate is consistent.
Those skilled in the art will be readily appreciated that, can carry out modification to the present invention under the situation of disclosed notion in not deviating from above specification sheets.This modification is believed to comprise in following claim, unless these claims are given explanation in addition by its language.Therefore, the specific embodiment of Xiang Ximiaoshuing only is illustrative here, does not limit the whole extensions and the given scope of the present invention of any and whole Equivalent thereof of claim subsequently.
Claims (22)
1. one kind prepares (S)-3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-method of 4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate, may further comprise the steps:
(a) make the reaction of 1,3-butadiene and ketone acetaldehyde compound form 2-carbonyl-3, the racemic mixture of 6-dihydropyrane compound;
Described ketone acetaldehyde compound is by following chemical formulation:
Wherein, R
1Expression hydroxyl, straight or branched C
1-C
12Alkoxyl group, unsubstituted or C
1-C
12Phenoxy group or group-NR that alkyl replaces
2R
3, R wherein
2And R
3Identical or different, hydrogen or C respectively do for oneself
1-C
12Alkyl or R
2And R
3Be combined together to form 2-12 unit ring, wherein one or more annular atomses are heteroatoms,
(b) with 2-carbonyl-3, the 6-dihydropyrane compound is converted into (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol;
(c) make the reaction of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol and trityl group chlorine contain 2-triphenyl methoxyl group-3, the solution of 6-dihydropyrane with formation;
(d) make 2-triphenyl methoxyl group-3,6-dihydropyrane and ozone reaction form reaction product;
(e) the described reaction product of reduction comprises the glycol of 3-(2-hydroxyl-oxethyl)-4-(triphenyl methoxyl group)-1-butanols with formation; With
(f) make the reaction of described glycol and sulfonyl methane based compound to form 3-[2-{ (methyl sulphonyl) oxygen } oxyethyl group]-4-(triphenyl methoxyl group)-1-1-butanol, methane sulfonate,
Wherein the alcohol that forms in dihydropyrane that generates in the step a) or the step b) comprises its racemic mixture, and described method also comprises the step that splits described racemic mixture so that (3, the 6-dihydro-2H-pyrans-2-yl) methyl alcohol that reacts in the step c) is made up of its S-isomer.
2. the process of claim 1 wherein that splitting step is at step a) and b) between carry out.
3. the process of claim 1 wherein that splitting step is at step b) and c) between carry out.
4. the method for claim 2, wherein splitting step comprises and makes 2-carbonyl-3, the resolved product composition that 6-dihydropyrane compound and lytic enzyme reaction have water and organic phase with generation.
5. the method for claim 4, wherein the R-isomer of racemic mixture is present in aqueous phase, and the S-isomer is present in the organic phase.
6. the method for claim 5 also comprises the step that water and organic phase are separated, and so just removes the R-isomer from the resolved product composition.
7. the method for claim 4, wherein lytic enzyme comprises proteolytic enzyme.
8. the method for claim 7, wherein proteolytic enzyme comprises bacillus lentus proteolytic enzyme.
9. the method for claim 4, wherein step b) comprises and makes 2-carbonyl-3,6-dihydropyrane compound and lithium aluminum hydride reaction.
10. the process of claim 1 wherein that step c) also comprises adds catalyzer in alcohol.
11. the process of claim 1 wherein that step d) comprises 2-triphenyl methoxyl group-3, the 6-dihydropyrane be dissolved in the solution and with the ozone bubbling by described solution to generate the solution of ozonize.
12. the method for claim 11, wherein step e) comprises in the solution of ozonize and adds reductive agent.
13. the method for claim 12, wherein reductive agent comprises sodium borohydride.
14. the process of claim 1 wherein R
1Be hydroxyl.
15. the process of claim 1 wherein that the ketone acetaldehyde compound comprises glyoxylic acid ethyl ester.
16. the method for preparation (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol isomer may further comprise the steps:
(a) make the reaction of 1,3-butadiene and ketone acetaldehyde compound form 2-carbonyl-3, the racemic mixture of 6-dihydropyrane compound; With
(b) with 2-carbonyl-3, the 6-dihydropyrane compound is converted into (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol,
Wherein the alcohol that generates in dihydropyrane compound that generates in the step a) or the step b) comprises its racemic mixture, and described method also comprises the step that splits described racemic mixture so that the alcohol that produces in the step b) is made up of its a kind of isomer.
17. the method for claim 16, wherein splitting step is at step a) and b) between carry out, described splitting step comprises with lytic enzyme handles 2-carbonyl-3, the racemic mixture of 6-dihydropyrane compound is to produce the resolved product composition, it has and comprises (3,6-dihydro-2H-pyrans-2-yl) water of a kind of isomer of methyl alcohol and the organic phase that comprises the another kind of isomer of (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol.
18. the method for claim 16, wherein said splitting step comprises makes (3,6-dihydro-2H-pyrans-2-yl) a kind of isomer in the methyl alcohol racemic mixture comprises reaction product and another kind of mixture of isomers with the compound of reaction reaction with generation in the presence of lytic enzyme, and described another kind of isomer is unreacted.
19. the method for claim 18, wherein said compound of reaction comprises vinyl-acetic ester.
20. the method for claim 19, wherein lytic enzyme comprises lipase.
21. the method for claim 20 also comprises unreacted isomer is separated from mixture.
22. the method for claim 16,2-carbonyl-3 wherein, the 6-dihydropyrane compound comprises a kind of 2-of containing alkoxy carbonyl-3, the racemic mixture of the ester of 6-dihydropyrane, described splitting step comprises:
(i) the described ester of hydrolysis is to produce 3, the racemic mixture of 6-dihydropyrane-2-carboxylic acid;
(ii) handle 3 with resolving agent, the racemic mixture of 6-dihydropyrane-2-carboxylic acid is to obtain containing 3, the mixture of a kind of isomer of 6-dihydropyrane-2-carboxylic acid and the reaction product of another kind of isomer;
(iii) make 3, the isomer of 6-dihydropyrane-2-carboxylic acid reacts to generate a kind of isomer of ester with alcohol; With
(iv) with a kind of isomer of step ester reduction (iii) with generation (3,6-dihydro-2H-pyrans-2-yl) methyl alcohol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/718,711 | 2000-11-22 | ||
| US09/718,711 US6300106B1 (en) | 2000-11-22 | 2000-11-22 | Method of preparing 3-[2-{(Methylsulfonyl)oxy}-ethoxy ]-4-(triphenylmethoxy)-1-butanol, methane sulfonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1633504A CN1633504A (en) | 2005-06-29 |
| CN1276978C true CN1276978C (en) | 2006-09-27 |
Family
ID=24887178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018207529A Expired - Fee Related CN1276978C (en) | 2000-11-22 | 2001-10-30 | Method of preparing 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol, methane sulfonate |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US6300106B1 (en) |
| EP (1) | EP1341927B1 (en) |
| JP (2) | JP4133328B2 (en) |
| CN (1) | CN1276978C (en) |
| AT (1) | ATE335090T1 (en) |
| CA (1) | CA2429775A1 (en) |
| DE (1) | DE60121994T2 (en) |
| DK (1) | DK1341927T3 (en) |
| ES (1) | ES2267857T3 (en) |
| PT (1) | PT1341927E (en) |
| WO (1) | WO2002059342A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2181999A1 (en) | 2008-11-03 | 2010-05-05 | Zentiva, A.S. | Method of manufacturing ruboxistarin |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2655341B1 (en) * | 1989-12-01 | 1992-02-21 | Rhone Poulenc Sante | DIHYDROPYRANIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE. |
| NZ323571A (en) * | 1995-11-20 | 1998-12-23 | Lilly Co Eli | Protein kinase c inhibitor |
| CZ150398A3 (en) | 1995-11-20 | 1998-12-16 | Eli Lilly And Company | Novel intermediates and their use for preparing n,n-bridge bisindolylmaleimides |
| US5721272A (en) * | 1996-11-18 | 1998-02-24 | Eli Lilly And Company | Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides |
-
2000
- 2000-11-22 US US09/718,711 patent/US6300106B1/en not_active Expired - Fee Related
-
2001
- 2001-10-30 PT PT01994173T patent/PT1341927E/en unknown
- 2001-10-30 WO PCT/US2001/047187 patent/WO2002059342A1/en active IP Right Grant
- 2001-10-30 CA CA002429775A patent/CA2429775A1/en not_active Abandoned
- 2001-10-30 CN CNB018207529A patent/CN1276978C/en not_active Expired - Fee Related
- 2001-10-30 DK DK01994173T patent/DK1341927T3/en active
- 2001-10-30 ES ES01994173T patent/ES2267857T3/en not_active Expired - Lifetime
- 2001-10-30 DE DE60121994T patent/DE60121994T2/en not_active Expired - Fee Related
- 2001-10-30 EP EP01994173A patent/EP1341927B1/en not_active Expired - Lifetime
- 2001-10-30 JP JP2002559825A patent/JP4133328B2/en not_active Expired - Fee Related
- 2001-10-30 AT AT01994173T patent/ATE335090T1/en not_active IP Right Cessation
-
2008
- 2008-04-23 JP JP2008112946A patent/JP2008263985A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CN1633504A (en) | 2005-06-29 |
| DK1341927T3 (en) | 2006-11-13 |
| JP2006506941A (en) | 2006-03-02 |
| EP1341927A1 (en) | 2003-09-10 |
| DE60121994D1 (en) | 2006-09-14 |
| US6300106B1 (en) | 2001-10-09 |
| JP4133328B2 (en) | 2008-08-13 |
| DE60121994T2 (en) | 2007-03-15 |
| ATE335090T1 (en) | 2006-08-15 |
| JP2008263985A (en) | 2008-11-06 |
| CA2429775A1 (en) | 2002-08-01 |
| WO2002059342A1 (en) | 2002-08-01 |
| PT1341927E (en) | 2006-12-29 |
| EP1341927B1 (en) | 2006-08-02 |
| ES2267857T3 (en) | 2007-03-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100654115B1 (en) | Process for the preparation of optically active 2-[6-hydroxymethyl-1,3-dioxan-4-yl]acetic acid derivatives | |
| EP0595868B1 (en) | Process for the preparation of (s)-4-[3-(5-methyl-2-phenyl-4-oxazolyl)- 1-hydroxypropyl]bromobenzene | |
| EP3164408B1 (en) | Novel method for producing (e,z)-7,9 dodecadienyl-1-acetate | |
| CN1276978C (en) | Method of preparing 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol, methane sulfonate | |
| CA2065433C (en) | Synthesis of aryl alkanediols having high optical purity | |
| EP0188235A2 (en) | Production of optically pure organoboranes | |
| EP1151992A1 (en) | Method for purifying and isolating (2s,3s)- or (2r,3s)-halohydrin derivatives | |
| CN1835918A (en) | Process for the preparation of racemic 2-[[2-(4-hydroxyphenyl)ethyl]thio]-3-[4-(2-[4-[(methylsulfonyl)oxy]phenoxy]ethyl)phenyl]-propanoic acid | |
| EP2097425A2 (en) | Method for production of functionalised organo monoalkoxy (or monohydroxy) silanes in particular alkenyls | |
| JP3950492B2 (en) | Method for producing optically active fluorinated alcohol | |
| JP2974181B2 (en) | A new method for producing cyclobutanol | |
| EP0842915B1 (en) | Optically active alcohol and process for the production thereof | |
| EP0292350A1 (en) | Process for the preparation of vitamin A and some of its derivatives | |
| JP4106079B2 (en) | Method for producing optically active epoxy alcohol | |
| JPH05501883A (en) | Protected Hydroxy Method for Alcohol-Ester Separation | |
| JPS6314720B2 (en) | ||
| JPH05155815A (en) | Production of glycerol derivative | |
| US6388097B1 (en) | Process for the preparation of β hydroxy-δ lactone using novel intermediates | |
| EP1234884B1 (en) | A process for the preparation of beta-hydroxy-delta-lactone using novel intermediates | |
| JP2838527B2 (en) | Production method of optically active compound | |
| JPH027578B2 (en) | ||
| JP2000016991A (en) | 2-(benzo[b]thiophen-5-yl)-2-hydroxyacetonitrile and its production, and production of 2-(benzo[b]thiophen-5-yl)-2- hydroxyacetic acid compound from the same | |
| JPH0948745A (en) | Production of carboxylic acid ester | |
| US20040049067A1 (en) | Process for the enantioselective synthesis of propargyl alcohol derivatives of R configuration from the racemic mixtures thereof | |
| JP2004035452A (en) | Method for producing alicyclic monoolefin methanol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |